FDA Defers Action on AT-GAA Treatment for Pompe Disease


AT-GAA, an Amicus Therapeutics treatment for late-onset Pompe disease consists of miglustat, an orally administered stabilizing agent, in combination with cipaglucosidase alfa, an infusion enzyme-replacing component.

Bradley Campbell, president and chief executive officer, Amicus Therapeutics

Bradley Campbell

The FDA has deferred action on the biologics license application of cipaglucosidase alfa, Amicus Therapeutics' investigational combination therapy for the treatment of late-onset Pompe disease. Because of COVID-19-related travel restrictions, the FDA was unable to conduct the required inspection of the WuXi Biologics manufacturing site in China during the review cycle, leading to the deferral.1

Amicus noted that the sole reason for the FDA-issued letter was the agency's inabiity to complete the manufacturing facility inspection, and not because of safety concerns. The FDA has not provided an anticipated action date; however, the agency will be engaged with Amicus to develop plans and logistics for a preapproval inspection plan.

"We are now one step away from the necessary approvals for AT-GAA in the US. We continue to believe this is a question of ‘when’ not ‘if’ AT-GAA will be approved and we will continue to work with great urgency to support the FDA’s completion of the final plant inspection necessary for approval so that this important new treatment option is made available for people living with Pompe disease in the United States," Bradley Campbell, president and chief executive officer, Amicus Therapeutics, said in a statement.1 "We are also very pleased with the progress of the regulatory review in the EU and look forward to a Committee for Medicinal Products for Human Use opinion by the end of the year. We remain committed to bringing AT-GAA to as many people living with Pompe disease around the world as quickly as possible.”

The applications for the combination approach were originally set to be reviewed in mid-2022, with the agency extending the period in May.2 Cipaglucosidase alfa is a recombinant human acid alpha-glucosidase, or rhGAA, enzyme with optimized carbohydrate structures, including bis-phosphorylated mannose-6 phosphate glycans. It was originally known as ATB200, while miglustat was known as AT2221.

Amicus recently announced data on the treatment in March, which were presented by Barry Byrne, MD, PhD, of the University of Florida Health, at the Muscular Dystrophy Association’s (MDA) Scientific and Clinical Conference 2022, from the its open-label ATB200-02 trial (NCT02675465) of ATA-GAA, which included a total of 28 patients across 4 patient cohorts consisting of 3 patient groups: ambulatory enzyme-replacement therapy (ERT)-experienced (Cohort 1, n = 17), which consisted of 11 enrollees, plus 6 more as an additional cohort; nonambulatory ERT-experienced (Cohort 2, n = 6); and ERT-naïve (Cohort 3, n = 5).3

Those in Cohort 1 received escalating doses of cipaglucosidase alfa (5, 10, 20 mg/kg), followed by 3 doses of 20 mg/kg, plus low-dose miglustat, followed by ongoing doses of 20 mg/kg cipaglucosidase alfa plus high-dose miglustat. On the other hands, those in Cohorts 2, 3, and 4 received 20 mg/kg cipaglucosidase alfa plus high-dose miglustat.

Functional outcomes data (n = 23) showed that there were durable mean improvements from baseline in the ambulatory patients. On 6-minute walk test (6MWT) distances, there were gains for 81% (13 of 16; 34 m improvement), 80% (8 of 10; 21 m improvement), and 75% (6 of 8; 48 m improvement) of patients in the ERT-experienced group at 12, 24, and 36 months, respectively Of those who were ERT-naïve, there were improved distances in 6MWT in 100% (6 of 6; 57 m improvement), 100% (5 of 5; 61 m improvement), and 80% (4 of 5; 44 m improvement) of patients at 12, 24, and 36 months, respectively.3

Additionally, ambulatory and nonambulatory patients, including ERT-experienced and ERT-naïve individuals, reported gains in strength testing as assessed by manual muscle testing (MMT), with improvements were maintained out to 36 months. Pulmonary function also improved in ERT-naïve patients and was generally stable in ERT-experienced patients.

The therapy was also assessed in a phase 3, double-blind, parallel-group PROPEL trial (NCT03729362), the findings of which suggested that AT-GAA improved motor and respiratory functions in Pompe disease compared with an approved ERT, alglucosidase alfa (Lumizyme; Sanofi).4 Those findings were presented at the MDA 2021, March 15-18, by Tahseen Mozaffar, MD, FAAN, interim chair of neurology, and director, UC Irvine-MDA ALS and Neuromuscular Center and UC Irvine Neuromuscular Program, University of California, Irvine.5

In PROPEL, 123 patients who were ERT experienced and naïve were randomly assigned 2:1 to coadministration of AT-GAA (n = 85) or alglucosidase alfa (n = 38) every 2 weeks, at 20-mg/kg doses for each group. They assessed the mean change in 6MWT and percent predicted forced vital capacity (FVC; sitting) from baseline to week 52. Secondarily they evaluated patients with the lower extremities manual muscle test (MMT); gait, stairs, Gower, chair test (GSGC); and Patient-Reported Outcomes Measurement Information System (PROMIS)-physical function and -fatigue.

At week 52, participants in the AT-GAA group showed clinical improvement on 6MWT (mean change, 20.8 m; SD, 7.2) compared with alglucosidase approved therapy (mean change, 7.6 meters; SD, 6.6) but this was not statistically significant (P = .072). A statistically significant improvement in FVC was observed for the AT-GAA group (–0.9 change; SD, 0.7) compared with the alglucosidase group (–4.0 change; SD, 0.8; P = .023).4,5

The safety profiles were similar between groups, with 81 (95.3%) treatment-related adverse events (TEAEs) in the AT-GAA group and 37 (97.4%) in the alglucosidase group. Of these TEAEs, 26 (30.6%) in the AT-GAA group and 14 (36.8%) in the alglucosidase group were potentially related to treatment. There were 8 (9.4%) serious TEAEs—1 (1.2%) potentially related to treatment—reported in the AT-GAA group, and 1 serious TEAE unrelated to treatment in the alglucosidase group. Three TEAEs led to study withdrawal, 2 (2.4%) in the AT-GAA group and 1 (2.6%) in the alglucosidase group, and none led to death.

1. US FDA defers action on filing for AT-GAA in late-onset Pompe disease. News release. Amicus Therapeutics. October 28, 2022. Accessed October 28, 2022. https://www.globenewswire.com/news-release/2022/10/28/2544135/0/en/U-S-FDA-Defers-Action-on-Filing-for-AT-GAA-in-Late-onset-Pompe-Disease.html
2. Amicus Therapeutics Receives Notification of PDUFA Date Extensions for AT-GAA. News release. Amicus. May 10, 2022. Accessed August 25, 2022. https://ir.amicusrx.com/news-releases/news-release-details/amicus-therapeutics-receives-notification-pdufa-date-extensions
3. Amicus Therapeutics Announces Positive Long-Term Data from Phase 1/2 Study of AT-GAA in Pompe Disease at the 2022 MDA Clinical & Scientific Conference. News release. Amicus. March 16, 2022. Accessed August 25, 2022. https://ir.amicusrx.com/node/21666
4. Schoser B, Roberts M, Byrne BJ, et al. Safety and efficacy of cipaglucosidase alfa plus miglustat versus alglucosidase alfa plus placebo in late-onset Pompe disease (PROPEL): an international, randomised, double-blind, parallel-group, phase 3 trial. Lancet Neurol. 2021;20(12):1027-1037. doi:10.1016/S1474-4422(21)00331-8
5. Mozaffar T, Bratkovic D, Byrne B, et al. Efficacy and safety of cipaglucosidase alfa/miglustat versus alglucosidase alfa/placebo in late-onset Pompe disease (LOPD): A phase 3 trial (PROPEL). Presented at MDA Clinical and Scientific Conference 2021; March 15–18. Poster 129.
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